Our long-term objective is to develop a comprehensive and effective therapy capable of achieving reproducible and reliable periodontal regeneration. In doing so, combined approaches of basic and clinical research are proposed. The specific aims are: 1) To determine if the epidermal growth factor-receptor (EGF-R) of periodontal ligament (PDL) fibroblasts is associated with maintaining the undifferentiated state of these cells, and to what extent the loss of EGF-R is related to their differentiation, 2) To investigate the regulation of expression and synthesis of EGF-R by retinoic acid and EGF [transforming growth factor (TGF)-alpha], and to understand the mechanism by which retinoic acid regulates EGF-R on PDL fibroblasts, 3) To evaluate the in vivo effects of platelet-derived growth factor-BB (PDGF-BB), a combination of PDGF-AA, PDGF-BB, EGF, and/or retinoic acid on periodontal regeneration of class- III furcation lesions created in the beagle dog. Also to evaluate the effects of a combination of PDGF-BB and insulin-like growth factor-I, and bone morphogenic proteins such as osteogenic protein-1 (OP-1) in the beagle dog model, and 4) To assess the efficacy of therapy using growth factor-modulated regeneration combined with the guided tissue method using barrier membranes in the beagle dog. In basic research, we propose to understand the role of the EGF-R on PDL fibroblasts in maintaining the undifferentiated state of PDL cells and regulating their differentiation into osteoblasts and possibly cementoblasts in vitro. Furthermore, the fundamental mechanism by which retinoic acid regulates the EGF-R gene will be investigated. For these purposes, techniques such as the ligand binding assay, in situ hybridization, immunoprecipitation, immunogold labeling, Northern blotting, transfection, oligonucleotide deletion analyses and gel retardation assay will be applied. These studies will help us to understand the basic mechanisms maintaining the phenotype of PDL cells and regulating their differentiation into osteoblasts and possible cementoblasts. This information may also lead to better understanding of bone cell differentiation. An effort will also be made to link the basic research to clinical application using the rat reimplantation and beagle dog models. Rapid repair of the PDL will be achieved by selective repopulation of PDL fibroblasts using guided tissue regeneration combined with growth factor- modulated method. The factor(s) capable of maintaining the undifferentiated state of PDL cells will be clinically applied to regulate orderly cell proliferation and migration, and prevent PDL cell premature differentiation into osteoblasts and thus, ankylosis during healing of the PDL. Such knowledge will be valuable for orderly regeneration of the tooth supporting tissues. These studies will promote advances in knowledge of the biology of the periodontium, and repair and regeneration of the periodontal tissues. Furthermore, this comprehensive periodontal regenerative therapy will contribute to achieving the oral health promotion objective of "Healthy People 2000" regarding reducing tooth loss due to periodontal disease.